Sitafloxacin hydrate has the chemical name of 7-[(7S)-7-amino-5-azaspiro[2.4]hept-5-yl]-8-chloro-6-fluoro-1-[(1R,2S)-cis-2-fluorocyclopropyl]-1,4-dihydro-4-oxo-3-quinoline carboxylic acid, which is a broad-spectrum quinolones antibacterial agent developed by Daiichi Sankyo and the monohydrate thereof is used clinically for the treatment of severe refractory infectious diseases. This product can be developed for oral administration or injection administration. The oral quinolones drug Gracevit (sitafloxacin) (I) has come into the market of Japan, which is the first market on the world. The compensation price is set at 228 yen (US $2.17) per 50 mg tablet and the price of one pack of 10 fine granules is set at 576 yen.
This product has good pharmacokinetic properties, and can alleviate adverse physiological response, the antibacterial activity in vitro of which is significantly improved compared to most similar drugs. This product not only has significantly enhanced antibacterial activities against Gram-positive bacteria, but also has antibacterial activities against many clinically isolated strains resistant to fluoroquinolones. The study on the antibacterial activities of this product in vitro proves that this product has broad-spectrum antibacterial activities, i.e. it not only has antibacterial activities against Gram-negative bacteria, but also has strong antibacterial activities against Gram-positive bacteria (methicillin-resistant staphylococcus aureus and methicillin-resistant staphylococcus epidermidis), anaerobic bacteria (including Bacteroides fragilis) and mycoplasma, chlamydia, etc., in addition, this product has good bactericidal effect on many clinically common fluoroquinolones-resistant strains. This product is well absorbed orally, has a bioavailability of more than 70%, and can be distributed to extensive tissues, wherein the drug concentrations in various tissues outside the central nervous system are higher than the drug concentration in serum. Therefore, this product is expected to become an important drug for the treatment of single or mixed bacterial infections in respiratory tract, urogenital tract, abdominal cavity as well as skin soft tissues, etc.
(7S)-5-azaspiro[2.4]heptane-7-yl-tert-butyl carbamate is an important intermediate of sitafloxacin, whose disadvantages are that the synthetic route is long and difficult to be resolved, etc., resulting in limited market capacity, and high price.
At present, there are several methods for synthesizing (7S)-5-azaspiro[2.4]heptane-7-yl-tert-butyl carbamate:
The first method comprises the steps of synthesizing racemates and then resolving them to give one compound with single-configuration. This method results in the waste of the other chiral compound.

In the second method, dangerous chemicals such as cyanides or nitromethane are used, which poses a great safety risk in production and is inconvenient for scale-up production (CN101544581A).

In the third method, a catalyst is used for reducing to directly obtain chiral amines, however, the reduction efficiency is still not high, and the ee value is only 53% (JP2004099609A).

In the fourth method, a beer yeast is used for reducing so as to obtain the chiral alcohols, and then Mitsunobu reaction is performed to obtain the chiral amines. This method has low reduction efficiency in volume and is difficult for scale-up production (Chem. Pharm. Bull. 1998, 46, 587).
The disadvantages of these methods are that it is difficult for scale-up production, resulting in that there is a very few manufacturers for producing (7S)-5-azaspiro[2.4]heptane-7-yl-tert-butyl carbamate, and the price is very high, which seriously hinder the further application and development thereof in organic chemistry and biomedicine. Therefore, it will have a great practical value to develop a process route that can be safely scaled up.